Project Summary Klinefelter Syndrome is a common chromosomal abnormality of males who have two X chromosomes XXY, rather than one, XY. XXY males experience a variety of congenital developmental problems, including infertility, lower levels of androgens, increased risk for obesity and metabolic disease, increased risk for autoimmune diseases, and cognitive features including alterations in executive function and delayed language development. The long-term objectives of this project are to identify X chromosome genes that cause behavioral features of Klinefelter Syndrome, using novel mouse models. An overarching question is to separate the direct effects of X chromosome genes that cause Klinefelter Syndrome traits, from those caused by lower testosterone levels in XXY individuals. A novel mouse model produces XXY, XY, and XX mice that have either testes or ovaries, so that sex chromosomal effects can be identified that do not require testicular secretions, or occur when testicular secretions do not explain differences. Mice will be compared in a series of Klinefelter Syndrome-relevant behavioral measurements that assess executive functions, development of vocalizations, and partner preference. The expression levels of six specific X chromosome genes, which are the major candidates for causing the features of Klinefelter Syndrome, will be directly manipulated to assess which is/are likely the causal genes in the mouse model.